This proposal represents a formalization of a group effort researching the fundamental features of Alzheimer's disease. Although broken down into five projects and a Core to facilitate review, the application seeks support for a highly integrated study of six major issues in Alzheimer's disease. Project #1 is concerned with the definition of the potential significance of a new protein recently discovered in the brains of patients with Alzheimer's disease. The work planned includes determining whether or not this protein occurs in the brains of patients with other neurologic diseases, the possible detection of this protein in spinal fluid and other tissues and fluids, and further characterization of the nature and function of the protein. Obtaining a cDNA probe for the gene for this protein and molecular genetic studies are also planned. In Project #2, antibodies raised to purified neurofibrilliary tangles are being used to screen human brain expression vector cDNA libraries for probes to components of the tangle. A series of probes is already under investigation, and further screening is planned. The aim is to determine in unambiguous fashion which epitopes are present in purified tangles. In Project #3, the nature and source of amyloid in neuritic plaques will come under study. New information suggesting the presence of amyloid or amyloid precursors in "primitive" neuritic plaques will be intensively investigated, and biochemical and molecular techniques will be employed to investigate the nature and source of amyloid fibrils. In Project #4, cytoskeletal studies will be extended to animals and peripheral fibroblasts from Alzheimer patients. In addition, calcium and metabolic homeostasis will be investigated following preliminary studies which clearly demonstrate abnormalities. In Project #5, a coordinated study aimed at identifying early stages of the cholinergic deficit in Alzheimer patients will be followed by attempts at treatment. Using our large available patient population, we will attempt to replicate the observation that a rare complement C4 component occurs with high frequency in patients with Alzheimer's disease. We hope to further unravel some of the fundamental problems apparent in research on Alzheimer's disease.